Abstract Women's Health Initiative Sequencing Project (WHISP) The overall goal of this project submitted in response to NHLBI RC2 Topic 'Large-scale DNA Sequencing and Molecular Profiling of Well-phenotyped NHLBI Cohorts'(RFA-OD-09-004) is to identify putative functional variants for high-priority heart lung and blood phenotypes among American post-menopausal women from diverse ancestral and geographic backgrounds. Increasingly, genome-wide association studies have reported associations of genetic variants with heart lung and blood related complex traits and diseases such as cardiovascular diseases (CVD), diabetes, and obesity. Many of these associations have been repeatedly confirmed in large studies and are considered "putative genuine variants". For these genes to be considered for clinical or preventive uses, identification of possible rare causal variants directly responsible for the disease- susceptibility is required. Indeed, a sequential strategy is best suited to characterize and catalogue the complete set of causal variants contributing to disease heritability and etiology. To fully examine the genetic architecture of CVD-related traits we will perform CVD phenotype-based resequencing for the unbiased discovery of rare variants having large effects in a subset of participants selected from the tails of multiple CVD related phenotypic distributions in the Women's Health Initiative (WHI) Clinical Trial (CT) (n=68,132) and Observational Study (OS) (n=93,676). We will then validate the newly discovered coding variants by performing selective genotyping in the remaining cohort and other populations selected by the study steering committee, toward a complete characterization of the set of causal variants contributing to disease heritability and development, and to further assess the role of these causal variants in relation to other CVD-related traits and pathways. We will also perform pathway analysis on selected variants to assess whether a particular pathway is enriched with disease risk-associated genes. The WHI is one of the most definitive, far-reaching population-based studies of post-menopausal women's health. This large and diverse study population not only enables us to identify novel rare variants that contribute to these phenotypes (specific aim 1) but allows us to validate these newly discovered coding variants in the remaining cohort participants to begin to characterize the complete set of causal variants contributing to disease heritability and etiology and to further assess the role of these causal variants in relation to other CVD-related traits and (specific aim 2). Information generated from this study will be critical to determine the health impact of any given undisputable variant. Findings may also provide valuable insights into disease pathways and mechanisms, and targets for disease screening, prevention, and treatment. PUBLIC HEALTH RELEVANCE: Genome-wide association studies have reported associations of genetic variants with heart lung and blood related complex traits and diseases such as cardiovascular diseases (CVD), diabetes, and obesity. For these genes to be considered for clinical or preventive uses, identification of possible rare causal variants directly responsible for the disease-susceptibility is required. To fully examine the genetic architecture of CVD- related traits, we propose to perform CVD phenotype-based resequencing followed by validation genotyping for the unbiased discovery of rare variants having large effects in a subset of participants with multiple CVD related phenotypic distributions in the Women's Health Initiative.